Methylphenidate Extended Release Chewable Tablet

ABSTRACT

An oral methylphenidate extended release tablet is described, which can be scored and still retain its extended release profile. The tablet contains a combination of an uncoated methylphenidate - ion exchange resin complex, a barrier coated methylphenidate - ion exchange resin complex -matrix, and an uncomplexed methylphenidate active component. Following administration of a single dose of the extended release methylphenidate chewable tablet, a therapeutically effective amount of methylphenidate is reached in less than about 20 minutes and the composition provides a twelve-hour extended release profile.

BACKGROUND OF THE INVENTION

Methylphenidate hydrochloride (HCl) and dexmethylphenidate hydrochlorideboth have the empirical formula C₁₄H₁₉NO₂•HCl. Methylphenidate HCl is aracemic mixture of d,1-threo-methyl α-phenyl-2-piperidineacetatehydrochloride. Several commercial products, including, e.g., Ritalin®,Daytrana®, and Metadate® contain methylphenidate HCl as the active drug.Dexmethylphenidate is the d-threo-enantiomer of racemic methylphenidatehydrochloride [Focalin ® product literature]. There are severalcommercial products which contain dexmethylphenidate as the active drug.

The use of the central nervous system stimulants methylphenidate anddexmethylphenidate for the treatment of such conditions as attentiondeficit disorder (ADD) and attention deficit hyperactivity disorder(ADHD) in adults and children has been described [see, Focalin®,Concerta®, Ritalin®, Daytrana® and Metadate® product literature]. Thisdrug may also be used to treat depression and cognitive impairmentfollowing Traumatic Brain Injury [See, product literature formethylphenidate hydrochloride tablet which is commercially availablefrom Lake Erie Medical DBA Quality Care Products LLC, and productliterature of the other drug products identified herein].

Solid dose methylphenidate or dexmethylphenidate products arecommercially available having an extended release profile of 8 hoursaccording to the product label. These products include, e.g., Ritalin®LA and Methylin® ER tablets have product labels indicating that theymust be swallowed whole without crushing or chewing. Liquidmethylphenidate dosage forms have also been described which arepredominantly designed for children, including children as young as 3years old who have difficulty swallowing solid dosage forms.

There remains a need for a quick-acting, stable, extended releasemethylphenidate product which can be conveniently delivered in a formsuitable for patients who have difficulty swallowing solid tablets andcapsules.

SUMMARY OF THE INVENTION

The present invention provides a methylphenidate extended releasechewable tablet which provides a fast onset of MPH and a twelve-hourrelease profile. The chewable tablet can be divided into portions andthese tablet portions retain the fast onset and 12 hour release profileof the intact tablet. In one embodiment, the tablet is scored tofacilitate splitting when desired. Methods of treating patients in needthereof with these methylphenidate (MPH) extended release chewabletablets are further provided by the invention.

The MPH extended release chewable tablet comprises (i) two differentimmediate release methylphenidate components, each of which provides adifferent immediate release profile, and (ii) about 50% to about 90% w/wof a sustained release barrier coated methylphenidate - ion exchangeresin complex - matrix, based on the total weight of the methylphenidatecomponents.

The first immediate release methylphenidate components is an uncoatedmethylphenidate - ion exchange resin complex, optionally in combinationwith a matrix forming polymer which is characterized herein as the“slower” onset immediate release component. The second immediate releasecomponent is a faster onset immediate release methylphenidate componentwhich is a methylphenidate, pharmaceutically acceptable salt thereof, orhydrate thereof as defined herein, which is not complexed with or boundto an ion exchange resin. The sustained release component has a barriercoating which is a pH-independent release, high tensile strength, waterinsoluble, water-permeable barrier coating.

In another embodiment, the invention provides a scored chewable tablet,wherein dividing the tablet does not significantly modify the in vitroprofile of the tablet portions resulting from split or other division ofthe intact tablet.

In one embodiment, a methylphenidate extended release chewable tabletcomprises methylphenidate components in a combination of (a) about 60%w/w - 80% w/w of a sustained release, cured, barrier coatedmethylphenidate - ion exchange resin complex -matrix, wherein thebarrier coating comprises polyvinylacetate and a plasticizer (b) about10% w/w to about 20% w/w of a combination of an immediate releaseuncoated methylphenidate - ion exchange resin complex and (c) about 10%w/w to about 20% w/w of an immediate release uncomplexedmethylphenidate. Throughout this specification, when weight percentagesand/or ratios are provided for methylphenidate in each of the threeactive components, the weights are based on the amount ofmethylphenidate base in each component. As used herein the term“uncomplexed methylphenidate” is referred to as the faster onsetimmediate release component and specifically includes a free basemethylphenidate, as well as a pharmacologically active andphysiologically compatible salt form thereof, including acid additionsalts, and hydrates thereof; specifically excluded from the term“uncomplexed methylphenidate” is a methylphenidate which bound to orcomplexed with an ion exchange resin.

In a further embodiment, the invention provides a method of treatingpatients with a disorder for which methylphenidate is regulatoryapproved by administering a methylphenidate extended release chewabletablet as described herein.

Still other aspects and advantages of the invention will be apparentfrom the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a linear plot of mean methylphenidate plasma concentrationversus time using non-transformed data. This study provides thepharmacokinetic (pK) profile of a single oral chewable tabletformulation of the invention dosed as described in Example 2 to providean amount of methylphenidate equivalent to a 40 mg dose ofmethylphenidate HCl. A commercially available immediate releasemethylphenidate HCl tablet (Methylin® 10 mg chewable tablet, 2×20 mgdelivered six hours apart (q6h)) was used as reference.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention provides a methylphenidate (MPH) extendedrelease chewable tablet. The MPH contains a combination of two differentimmediate release MPH components and a sustained release MPH component.Suitably, following administration of a single dose of the oral MPHextended release chewable tablet, in some embodiments, a therapeuticallyeffective amount of MPH is reached in less than about thirty minutes,and as soon as about twenty, ten, or fewer minutes, and the formulationprovides an extended release profile to at least about 12 hours.

The MPH extended release chewable tablets of the present invention aretypically prepared as single uniform solid dispersion compressed into achewable tablet. Suitably, the chewable tablet of the invention is auniform solid dispersion which provides extended release properties evenwhen scored such that when divided the separated tablet portions retainthe extended release profile described herein. In one embodiment, thechewable tablet has a hardness of about 5 kilopond (kp) to about 25 kp,about 8 to about 20 kp, or 10 to about 16 kp. One (1) kilopond is onekilogram of force (kgf). Newtowns (N) are the SI unit of force and theSI standard for tablet hardness testing. 1 kilopond (kp) is equal to9.80665 Newtons (N). Presented in Newton rounded to the nearest five,the chewable tablet has a hardness of about 45 N to about 245 N, about75 N to about 200 N, or about 95 N to about 160 N. Optionally, thehardness may be dose proportional, with lower doses having lowerhardness levels. For example, a 20 mg chewable tablet may have ahardness in the range of about 10 to about 12 kp (about 98 N to about118 N), a 30 mg tablet may have a hardness in the range of about 12 toabout 14 kp (about 118 N to about 137 N), and a 40 mg tablet may have ahardness in the range of about 14 kp to about 16 kp (about 137 N toabout 156 N). In one embodiment, the hardness is determined followingcompression and prior to application of any color or othernon-functional tablet coating as defined herein. In one embodiment, thetablet portions meet the USP Friability requirement. In one embodiment,the friability of both the intact tablet and the tablet portions areless than about 1.

A chewable tablet of the invention is distinguished from a rapiddissolve tablet or an orally dissolving tablet (ODT) by not dissolvingin the mouth in less than 1 minute, and more generally, not breakingapart or dissolving in the oral cavity in less than about 3 to about 5minutes without being chewed.

As used herein “methylphenidate” includes the free base form of theactive ingredient which is either (i) racemic mixture of two opticalisomers d-threo-methylphenidate and 1-threo-methylphenidate or (ii) theactive isomer d-threo-methylphenidate (also known asdexmethylphenidate). For convenience, methylphenidate is abbreviated“MPH” herein. When reference is made herein to methylphenidate or MPH,it will be understood that either the racemic mixture (typically 50/50d- to 1-) or dexmethylphenidate is encompassed by this term. Where onlythe racemate or dexmethylphenidate is desired, reference will bespecifically made to one or the other. Thus, for the formulationsdescribed herein, the methylphenidate may be independently selected fromracemic methylphenidate (e.g., a 50/50 mixture of D-methylphenidate andL-methylphenidate), and dexmethylphenidate. Whether selected from theracemate or dexmethylphenidate, the active drug may be present in theform of a salt or a hydrate. One suitable salt is the HCl salt form.However, other salts may be selected, e.g., the acetate salt, themaleate salt or any other pharmaceutically acceptable acid additionsalt. Methylphenidate may be purchased commercially, e.g., as thehydrochloride salt thereof. Alternatively, the MPH may be prepared usingmethods known to those of skill in the art. Processes for the synthesisof methylphenidate and its analogs have been described. See, e.g., WO2010/080787; U.S. Pat. Nos. 2,507,631 and 2,957,880, as have processesfor synthesis of threo-methylphenidate and its d- enantiomer have beenreported and which are incorporated herein by reference. See, e.g., U.S.Pat. Application Publication No. 2006/0135777, which is incorporatedherein by reference.

As used herein, the term “free methylphenidate” refers to the weight ofthe methylphenidate base, i.e., exclusive of any salt or complex form.

In one embodiment, a MPH extended release chewable tablet the inventioncontains a methylphenidate in three different forms, (a) a sustainedrelease barrier coated MPH – ion exchange resin complex, optionally in amatrix, (b) an slower onset immediate release uncoated MPH – ionexchange resin complex, optionally in a matrix, and (c) a faster onsetimmediate release uncomplexed MPH. While the source of the MPH in theworking examples herein was the same, it will be understood that the MPHcan be independently selected for each of component (a), (b) and (c).For example, the complexes of each (a) and (b) may be produced using thesame MPH (e.g., racemic MPH) and (c) may be a different MPH (e.g.,dexMPH). Alternatively, the complexes of each of (a) and (b) may beproduced using different MPH and the MPH of (c) may be independentlyselected.

As used herein, the term “extended release” (“ER”) refers tocompositions which are characterized by having at least one of theactive components (i.e., MPH or dexMPH) having a release over a periodof at least about 12 hours. As with formulations described herein,“extended release” may be achieved by a single formulation containingtwo “immediate release” components and a “sustained release” (i.e.,release for about 12 hours). The release profile may be assessed via invitro dissolution using techniques known to those of skill in the art[e.g., USP basket method, Paddle Method, channel flow method, or othermethods known in the literature]. The release profile can be assessed invivo (e.g., for bioavailability determinations), using plasmaconcentrations to assess maximum plasma concentration (C_(max)) and areaunder the curve (AUC). Such assays are well known to those of skill inthe art. [see, e.g., W. Wargin, et al., Pharmacokinetics ofmethylphenidate in man, rat and monkey. J Pharmacol Exp Ther August 1983226:382-386].

The term “immediate release” (“IR”) is the release of an activeingredient (e.g.., MPH) from a pharmaceutical formulation where the rateof release of the active pharmaceutical ingredient from thepharmaceutical formulation is not retarded by means of a controlledrelease matrix or other such means and where the components of thepharmaceutical formulation are designed such that, upon ingestion,maximum exposure of said active pharmaceutical ingredient to bodytissues occurs in the minimum period of time. As described herein, an“immediate release” MPH component preferably releases in less than 1hour. The present invention provides for an extended release chewabletablet having two different immediate release MPH components, each ofwhich provides a different release profile.

Suitably, one of the immediate release components provide a fasteronset, i.e., release and therapeutic effect in less than 30 minutes,preferably, less than 20 minutes and in as few as ten minutes, orsooner. This immediate release component is an uncomplexed MPH which isdefined in the specification. A second, different, immediate releasecomponent provides a different immediate release pharmacokineticprofile, which releases in less than about an hour, as soon as about 45minutes, or as soon as about 30 minutes. Typically, this immediaterelease component does not release as quickly as the faster onsetcomponent. Suitably this slower onset immediate release component is anuncoated MPH - ion exchange resin complex, which is optionally in amatrix with a matrix forming polymer. When present in the immediaterelease component, the matrix forming polymer is selected so that theresulting uncoated MPH - ion exchange resin complex (optionally in amatrix) retains an immediate release profile. For convenience, theoptional matrix is not referenced in every phrase where the uncoatedcomplex is discussed. However, it will be understood that this uncoatedcomplex may contain such a component. The release profiles of the twodifferent immediate release components may overlap.

In one embodiment, the faster onset immediate release component(uncomplexed MPH) releases almost 100% of the MPH within about the firsttwenty to thirty minutes following administration. In anotherembodiment, the slower onset immediate release uncoated MPH - ionexchange resin complex releases at least about 50% of the MPH withinabout the first hour following administration, and at least about 80% ofthe MPH within about 90 minutes following administration.

In one example, the sustained release barrier coated MPH - ion exchangeresin complex, optionally in a matrix is present in an amount of about50% w/w to about 90% w/w, about 60% w/w to about 80% w/w, or about 68%w/w to about 72% w/w of the MPH components in the chewable tablet. Thetwo immediate release components combine to provide about 10% w/w toabout 50% w/w, about 20% w/w to about 40% w/w, or about 25% w/w to about30% w/w of the MPH components in the chewable tablet. The uncoated MPH-ion exchange resin complex component is designed to be immediaterelease as defined herein, and as such, does not contain a coating whichfunctions to delay release (e.g., no functional amount of an extendedrelease barrier coating or enteric coat). Suitably, immediate releaseMPH - ion exchange resin complex is present in an amount of about 5% w/wto about 30% w/w, or about 10%w/w to about 20% w/w, of the MPHcomponents in the chewable tablet. The extended release component andthe immediate release MPH- ion exchange resin complex are further incombination with an uncomplexed MPH drug. The other IR component, whichis uncomplexed MPH drug, is present in an amount of about 5% w/w toabout 30% w/w, or about 10%w/w to about 20% w/w, of the MPH componentsin the chewable tablet. In one embodiment, the weight percentages of MPHcontributed by each of the two immediate release components are thesame. However, in other embodiments, it may be desirable to provide MPHin the immediate release components in different weight percentages.

When expressed as a ratio, the ratio of the two immediate releasecomponents comprise MPH in a ratio of uncoated MPH- resin complex(optionally in a matrix) to that in uncomplexed methylphenidate in thechewable tablet is generally in the range of about 6:1 (uncoated MPHcomplex: uncomplexed MPH) to about 1:6 (uncoated MPH complex:uncomplexed MPH), or about 2:1 to about 1:2. In one embodiment, theratio of extended release coated MPH - resin complex to uncoated MPHcomplex is in the range of about 18:1 (coated MPH: uncoated MPH complex)to about 5: 3 (coated MPH complex: uncoated MPH complex), or about 8:1to about 3:1.

In one embodiment, the ratio of MPH in coated MPH – resin complex:uncoated MPH – resin complex: uncomplexed MPH is 80:10:10 to about70:15:15. However, other suitable ratios, including those in which theMPH in the two immediate release components differ from each other, maybe selected within the ranges provided herein.

The term “initial administration” is defined for purposes of the presentinvention as the first single dose of a formulation containing an activeingredient administered to a patient or subject or the first doseadministered to a patient or subject after a suitable washout period.

As is often the case with psychoactive drugs, a therapeutic result forMPH is not solely related to plasma levels of the drug. Thus, “atherapeutically effective amount” of MPH includes the minimum amount ofthe drug required to provide a clinically observable psychologicaland/or behavioral response. A therapeutically effective amount of MPHcan alternatively be defined as being at least the minimum amount of MPHwhich reduces or eliminates the symptoms associated with a condition forwhich MPH has been approved for use. Appropriate doses are discussed inmore detail later in this specification.

Additionally, because the chewable MPH tablet described herein retainsits extended release properties even when scored. Further, evenfollowing being divided into other suitable portions, it is convenientfor physicians to reduce the dose for patients to introduce the drug ina smaller dose or incremental doses of medication for patients whoseneeds dictate such. This ability to divide the dose into portions allowsphysicians to take into consideration individual patient needs,including factors like age, body weight and individual response to themedication without the need for taking multiple doses over a twelve hourperiod of another product which offers only immediate release.

A “methylphenidate - ion exchange resin complex” refers to the productresulting from loading a methylphenidate salt onto a cation exchangeresin. Methods for preparing such complexes have been described, e.g.,in WO 2007/109104, incorporated herein by reference. This describes thecomplexation which occurs when the active and the ion exchange resin aremixed together in an aqueous medium to facilitate the “exchange” betweenthe salt of the MPH and the “cation” of the ion exchange resin and theformation of the complex, which may be referred to as “methylphenidatepolistirex”.

WO 2007/109104 also describes polyvinylacetate-based barrier coatingswhich are particularly well suited for use in the formulations describedherein to provide a sustained release coat over the MPH – ion exchangeresin complex – matrix. However, one skilled in the art can select otherbarrier coatings to provide the sustained release characteristics to MPH– ion exchange resin complex – matrix.

As used herein, a “precoated” MPH - ion exchange resin complex or a“precoated” MPH – ion exchange resin complex – matrix refers to aparticle which is to be subsequently coated with a barrier coating asdefined herein. In some embodiments, where the MPH – ion exchange resinor MPH – ion exchange resin complex – matrix is to be used as one of theimmediate release components and no barrier coating is to be applied, itis referred to as “uncoated”.

As used herein, a barrier coat is a water-permeable, water-insoluble,pH-independent polymer or co-polymer which in the present inventionconfers sustained release to the coated MPH – ion exchange resin complex– matrix. In one embodiment, the barrier coat is pH-independent,non-ionic and is applied, e.g., as an aqueous suspension, over theprecoated MPH – ion exchange resin complex – matrix and forms a separatelayer thereon. In another embodiment, the barrier coat ispH-independent, non-ionic and is applied as a solvent-based coating,over the precoated MPH – ion exchange resin complex - matrix and forms aseparate layer thereon. In still another embodiment, the barrier coat ispH-independent, ionic and is applied over the precoated MPH – ionexchange resin complex – matrix to form a separate layer thereon.Preferably, the barrier coat is directly over the precoated MPH – ionexchange resin complex– matrix and the barrier coat layer, i.e., thereare no intervening layers between the barrier coat and the precoated MPH– ion exchange resin complex – matrix. Depending upon the polymericmaterial selected, the barrier coat polymer or co-polymer may be curedto maximize their properties depending on the barrier coating selected.These polymers and their curing requirements are discussed in moredetail elsewhere in this specification.

A “methylphenidate - ion exchange resin complex - matrix” refers a MPH –ion exchange resin complex which is further combined, e.g., prior to orduring granulation, with a polymeric material which forms a matrix withthe MPH – ion exchange resin complex.

In one embodiment, a “methylphenidate polistirex” refers to the complexformed by loading a methylphenidate onto or reacting a methylphenidatewith an ion exchange resin. This term and the term “MPH – ion exchangeresin complex” may be used interchangeably throughout this document.

The term “matrix forming polymer” or “matrix forming polymeric material”refers to both water-insoluble polymers/co-polymers and water-solublepolymers/co-polymers which form a matrix with the MPH – ion exchangeresin complex upon being admixed or granulated therewith. Suitably, thematrix forming polymer is non-reactive with the MPH and the ion exchangeresin. The matrix forming polymer may be a water-insolublepolymers/copolymers and polymer systems which have been described asrelease retardants [see, e.g., polymers discussed in U.S. Pat.8,062,677, incorporated herein by reference], and those hydrophilicpolymer systems which have been described in the literature asimpregnating or solvating agents [see, e.g., polymers discussed in U.S.Pat.8,062,677 and U.S. Pat. 4,221,778, incorporated herein byreference]. In one embodiment, a MPH – ion exchange resin complex –matrix may include more than one matrix-forming polymer system. Forexample, an MPH – ion exchange resin complex – matrix may contain both ahydrophilic polymer and a hydrophobic polymer. An immediate release“uncoated methylphenidate - ion exchange resin complex” may optionallybe in a matrix. In this instance, the matrix forming polymer does notalter the ability of component to provide an immediate release profile.For example, a polyvinylpyrrolidone may be selected. However, the matrixforming polymer may alter the release rate of this complex while stillmaintaining an immediate release profile as defined herein.

The following terms are used in the specification and are to beinterpreted in accordance with the definitions herein.

“C_(max)” is the maximum observed plasma concentration, calculated asthe geometric mean of the individual maximum blood plasmaconcentrations.

The term “mean maximum plasma concentration” (mean C_(max)) is definedfor the purposes of the present invention as the maximum mean plasmadrug concentration.

“Mean plasma concentration” is the geometric mean blood plasmaconcentration.

The term “T_(max)” is the time at which the peak (maximum) observedblood plasma drug concentration for each individual participating in thebioavailability study.

The term “AUC_(0-∞)” or “AUC_(inf)” is the mean area under the plasmaconcentration-time curve extrapolated to infinity. It is calculated asthe arithmetic mean of the area under the plasma concentration-timecurve from time 0 extrapolated to infinity, calculated for eachindividual participating in the bioavailability study.

AUCpR is the area under the curve to the population median T_(max) ofthe reference formulation. AUC_(0-t) is the area under theplasma/serum/blood concentration-time curve from time zero to time t,where t is the last time point with measurable concentration forindividual formulation.

T/R ratio refers to the test formulation (MPH ER chewable tablet (40 mg)to reference (R) formulation (Methylin® IR 10 mg chewable tablet).

Intra-subject CV% refers to the geometric (CV) coefficient of variationbetween subjects.

The term “half-life” is the apparent terminal elimination half-life(T_(½)).

The words “comprise”, “comprises”, and “comprising” are to beinterpreted inclusively rather than exclusively. The works “consist”,“consisting”, and its variants, are to be interpreted exclusively,rather than inclusively.

As used herein the term “about” means a variability of 10% from thereference given, unless otherwise specified.

Methylphenidate/Dexmethylphenidate - Ion Exchange Resin Complex

A selected MPH can be complexed with, or loaded onto, a cation exchangeresin, using methods which are known in the art. See, e.g., WO2007/109104, and the documents cited therein. Cationic exchange resinsare readily selected for use as described herein.

A number of the processing steps described herein, including, e.g.,loading, pre-washing, complexing and granulation may be carried out in amulti-purpose apparatus, e.g., such as the PEF 450 processor [PallSeitzSchenk] or another similar and larger scale multi-purpose apparatuswhich is available commercially [e.g., by Rosenmund, U.S. Pat. No.5,609,835]. The vessel is capable of or adapted for pivoting and has asingle chamber with the capacity for handling areaction/crystallization, filtration, resuspension, and drying. Such avessel is typically provided with a water jacket connected with athermostatically controlled heating and cooling system. Alternatively,the processing steps described herein may be carried out in another typeof apparatus, or other multiple different apparatus, such as are knownin the art.

Ion Exchange Resins

Cationic exchange resins vary in strength, i.e., in their ability toexchange cations. In one embodiment, a relatively strong cationic resin,e.g., Amberlite® IRP69, manufactured by Rohm and Haas (a sulfonatedcopolymer of styrene and divinylbenzene) is selected. Alternatively, onemay select a relatively weak cationic exchange resin, e.g., Amberlite®IRP88 [Rohm and Haas, a crosslinked polymer of methacrylic acid anddivinylbenzene)], a weakly acidic (potassium ion) cation exchange resinwith 4% cross-linked methacrylate (100 to 500 mesh, equivalent to about150 microns to about 27 microns, ASTM standard) or Amberlite® 64 (amethacrylic acid and divinylbenzene polymer (hydrogen ion) polyacrilexresin, Rohm and Haas, with a particle size ranging from 100 to 400 mesh(equiv to 35 microns to 150 microns, ASTM standard size), capacity ~10meq/g by dry weight). Further, either regularly or irregularly shapedparticles may be used as cation exchange resins according to the presentinvention. Regularly shaped particles are those particles thatsubstantially conform to geometric shapes such as spherical, elliptical,cylindrical and the like, which are exemplified by Dowex® 50WX8 (The DowChemical Company). Irregularly shaped particles are all particles notconsidered to be regularly shaped, such as particles with amorphousshapes and particles with increased surface areas due to surfacechannels or distortions. Irregularly shaped ion-exchange resins of thistype are exemplified by Amberlite® IRP-69 (manufactured by Rohm & Haas),the use of which is illustrated in the examples below. This cationexchange resin is a sulfonated polymer composed of polystyrenecross-linked with about 8% of divinylbenzene, with an ion-exchangecapacity of about 4.5 to 5.5 meq/g of dry resin (H⁺-form). Anothercation exchange resin having similar properties is Dowex® 50WX8 (H+form, linear formula, C₁₀H₁₂ · C₁₀H₁₀ · C₈H₈)_(x), 200-400 mesh particlesize, which is equivalent to about 75 microns to about 35 microns, ASTMstandard). Amberlite® IRP-69 consists of irregularly shaped particleswith a size range of about 100 to about 500 mesh (about 150 microns toabout 27 microns, ASTM standard). Dowex® 50WX8 is more regularly shaped.Resins are generally purchased with a size ranging from about 25 micronsto about 400 microns. However, other sizes may be selected, or largersized particles may be milled to provide smaller particle sizes.

The selected ion-exchange resins may be further treated by themanufacturer or the purchaser to maximize the safety for pharmaceuticaluse or for improved performance of the compositions. Impurities presentin the resins may be removed or neutralized by the use of commonchelating agents, anti-oxidants, preservatives such as disodium edetate,sodium bisulfite, sodium metabisulfite, and so on by incorporating themat any stage of preparation either before complexation or duringcomplexation or thereafter. These impurities along with their chelatingagent to which they become bound may be removed before further use ofthe ion exchange resin.

The amount of methylphenidate that can be complexed with a resin willtypically range from about 5% to about 50% by weight of the MPH - ionexchange resin complex particles. A skilled artisan with limitedexperimentation can determine the optimum loading for any MPH - ionexchange resin complex. In one embodiment, loading of about 10% to about40% by weight, more desirably, about 15% to about 30% by weight, orabout 25% of the MPH - ion exchange resin complex particles can beemployed. In one embodiment, a composition of the invention contains MPHcomplexed to a sodium polystyrene sulfonate resin in at a ratio of 20MPH (based on the weight of the MPH salt) to 300 resin to 80 MPH (basedon the weight of the MPH salt) to 100 resin. In another embodiment, theMPH (based on the weight of the MPH salt) to resin ratio is 4:10 to1:10, or about 4:10 to about 2:10. In a further embodiment, the dexMPHpermits the use of about half the amount of active required when racemicMPH is the active drug.

In one embodiment, following complexation, a MPH - ion exchange resincomplex may be, in no particular order, milled to achieve a desired sizerange and dried (e.g., to a moisture content below about 10%, e.g.,about 3% to about 7%), and then stored for future use. In oneembodiment, the complex is milled or passed through a sieve to provide aparticle size ranging from about 40 microns to about 410 microns toenhance mouth feel (i.e., texture), or about 50 microns to about 250microns. These particles may be either regularly or irregularly shaped.In some embodiments, the average particle size of the uncoated MPH -ionexchange resin complex or the average particle size of the coated MPHion exchange resin complex is milled to a size of about 100 to about 200microns. These particle sizes maybe determined using sieve analysisthrough a sieve shaker having USP standard wire mesh sieves conformingto ASTM specifications.

In one embodiment, a matrix forming polymer is combined with the MPH -ion exchange resin complex following only partial complexation, or byreducing the moisture content of the wet MPH - ion exchange resincomplex to a range of between about 15 to about 25%, or another suitableamount. Treatment of the MPH - ion exchange resin complex with thematrix forming polymer is as follows.

MPH - Ion Exchange Resin Complex - Matrix

Optionally, a matrix-forming polymer is used to assist in processing anuncoated or precoated MPH - ion exchange resin complex. For example, amatrix-forming polymer may be used to facilitate granulation of theimmediate release MPH component (e.g., an uncoated MPH - ion exchangeresin complex). Alternatively, the matrix-forming polymer may be usedfor another purpose.

In one embodiment, a polyvinylpyrrolidone polymer [e.g., such as may bepurchased commercially as Kollidon® 30] is combined with themethylphenidate - ion exchange resin complex in order to facilitategranulation prior to coating. Other hydrophilic polymeric granulatingagents may include water-soluble polymeric materials which have beendescribed in the art as impregnating agents or solvating agents andwhich function in the present application as granulating agents. In oneembodiment, the granulating agent is a polyethylene glycol. Examples ofdesirable impregnating/solvating agents include those described in U.S.Pat. Application No. 11/724,966, filed Mar. 15, 2007, Published as US2007-0215511A, Sep. 20, 2007, and Meadows, US 2003-0099711, which areincorporated herein by reference, or in U.S. Pat. No. 4,221,778 andpublished U.S. Pat. Application Publication No. US 2003/0099711 A1, thedisclosures of which are incorporated herein by reference. Specificexamples of other impregnating agents include propylene glycol,polyethylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose,hydroxypropyl cellulose, and sorbitol.

Optionally, the MPH release rate from the compositions of the presentinvention may be admixed or granulated with a water-soluble orwater-insoluble polymer or a combination of a water-insoluble polymersprior to the application of the water-permeable diffusion barriercoating described herein. Upon admixture, these polymers do not form aseparate layer on the MPH - ion exchange resin complex, but form amatrix therewith. Examples of suitable matrix forming polymers include,for example, a polyvinyl acetate polymer or a mixture of polymerscontaining same (e.g., KOLLICOAT® SR 30D), cellulose acetates,ethylcellulose polymers (e.g., AQUACOAT® ECD-30 or SURELEASE®), acrylicbased polymers or copolymers (e.g., represented by the EUDRAGIT familyof acrylic resins), cellulose phthalate, or any combination of suchwater-insoluble polymers or polymer systems. These matrix-formingpolymers when used may further prolong or alter the release of the MPHfrom the ion exchange resin complex/matrix and maximize attaining thedesired release profile. One suitable polymer is a polyvinyl acetatepolymer as described herein or an acrylic polymer from the EUDRAGITfamily. Examples of suitable acrylic polymers from the EUDRAGIT familymay include, e.g., a copolymer comprising ethyl acrylate and methylmethacrylate (e.g., EUDRAGIT® NE-30D), or EUDRAGIT® RS30D, RL30D, whichare largely pH-independent polymers. EUDRAGIT® RS30D is a 30% aqueousdispersion of poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) in a ratioof 1:2:0.1; other aqueous dispersions of this copolymer may be selected.Eudragit® RL30 D is a 30% aqueous dispersion of poly (ethylacrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylatechloride) 1:2:0.2; other aqueous dispersions of this copolymer may beselected for use in the invention. Although less desirable, certainpH-dependent (enteric) polymers including, e.g., members of the EUDRAGITpolymer family, e.g., the L, S, and E, polymers and others which arecommercially available may be selected.

The quantity of polymer that is added to an uncoated or precoated MPH -ion exchange resin complex as a matrix forming polymer typically rangesfrom about 1% to about 30%, or about 3 to about 20%, or about 3 to about10%, about 10% to about 15%, about 15 to 25%, or about 1 to about 5% ormore by weight of the uncoated or precoated MPH - ion exchange resinparticulates prior to their being coated. However, higher or loweramounts may be selected. In one embodiment, where it is desired for thematrix forming polymer to have little or no effect on release rate, ahydrophilic polymer may be selected and used in a higher amount, whereasa hydrophobic release retardant if selected for use will be used at alower amount. Following admixing, the uncoated or precoated MPH - ionexchange resin complex particles with the matrix forming polymer, themixture is dried and the MPH -ion exchange resin complex - matrixgranules are milled appropriately to the desired particulate size.

For the precoated MPH - ion exchange resin complex - matrix which willbe coated and the uncoated MPH - ion exchange resin complex, theparticles are milled though a size below about 410 microns, or generallyin the range of about 50 microns to about 410 microns, or about 100microns to about 410 microns. This can be achieved, e.g., using a CO-MILdevice fitted with a 40 mesh screen. In one embodiment, the particleshave an average size of about 100 to about 250 microns, or about 100 toabout 200 microns. In some cases, the milling may be carried out beforethe complete drying of the complex or complex matrix and then againfurther drying followed by milling to obtain the desired complexcharacteristics. These particle sizes maybe determined using sieveanalysis through a sieve shaker having USP standard wire mesh sievesconforming to ASTM specifications.

Barrier Coat for Sustained Release

The sustained release component of a MPH chewable tablet of theinvention contains a methylphenidate - ion exchange resin complex -matrix with a barrier coating which modifies the release profile of themethylphenidate - ion exchange resin complex - matrix such that themethylphenidate has about a 12 hour sustained release profile. Suitably,the barrier coating has a pH-independent release (i.e., it is not anenteric coating which has pH-dependent release) and is awater-insoluble, water-permeable coating material. In a preferredembodiment, neither the chewable tablet nor any of its components has anenteric coating.

Suitably the properties of the barrier coating provide sustained releaseproperties to the barrier coated MPH - ion exchange resin complex, whichis MPH - ion exchange resin is optionally in matrix. When the matrix ispresent, the barrier coating is applied over the MPH - ion exchangeresin complex - matrix. The barrier coating provides the sustainedrelease component with resistance to grinding forces which enables theportions of a chewable tablet of the invention to provide a sustainedrelease MPH profile even when cut into pieces.

The barrier coating has a characteristic high flexibility or elongation(elasticity) at break measured by the texture analyzer TA-XT2 HiR(Stable Microsystems) and by the method reported by the manufacturer inits literature [i.e., Jan-Peter Mittwollen, Evaluation of the MechanicalBehavior of Different Sustained Release Polymers, Business Briefing:Pharmagenerics, 2003, pp. 1-3, BASF], with a tensile strength in a rangeof at least about 150% to about 400%. When the polyvinylacetate basedbarrier coating described herein is selected, this is achieved while notsubstantially increasing the tackiness of the polymer film greater thanabout 2 (wherein the film is measured by the Hössel method referencedabove independent of any composition on which it has been deposited).

In one embodiment, the barrier coating layer is about 10% to about 70%,by weight, or about 15% to about 65%, by weight, of the precoatedmethylphenidate - ion exchange resin complex - optional matrix in orderto provide the sustained release component. In another embodiment, thebarrier coating layer is about 20% to about 50%, about 25% to about 40%by weight, about 25% to about 35% by weight, or about 30%, by weight ofthe precoated methylphenidate - ion exchange resin complex - optionalmatrix (i.e., prior to coating). Still other suitable ranges can bedetermined by one of skill in the art, having been provided with theinformation herein.

The barrier coating is applied over the uncoated or precoated MPH - ionexchange complex - optional matrix (e.g., as an aqueous dispersion or asolution), dried, and milled or passed through a screen such that thebarrier coated MPH – ion exchange complex - optional matrix particlesare in the same size range as described in the preceding paragraph,i.e., in the range of about 50 to about 410 microns.

In one embodiment, the barrier coating is applied as an aqueousdispersion which is dried in order to provide the desired sustainedrelease profile. In the case of an aqueous -based polyvinylacetatecoating, the coating is cured in order to provide the desired releaseprofile.

In one embodiment, the barrier coating is applied as an aqueousdispersion of a water insoluble polymer comprising a polyvinyl acetatepolymer, or a blend of polymers comprising a polyvinyl acetate polymer.In one embodiment, the barrier coating further contains a plasticizer,which can facilitate uniform coating of the MPH - ion exchange resincomplex and enhances the tensile strength of the barrier coating layer.

One coating composition useful in the present invention is applied inthe form of an aqueous dispersion containing polyvinylacetate (PVA)polymer based aqueous coating dispersion and a plasticizer. The PVA isinsoluble in water at room temperature. The PVA may be used in eithersubstantially pure form or as a blend. Where the barrier coatingcomprises a PVA polymer, the PVA polymer is present in an amount ofabout 70% to about 90% w/w of the final barrier coating layer, at leastabout 75%, at least about 80%, about 85% w/w of the final barriercoating layer. Generally, a plasticizer is used in the percent range, ora mixture of plasticizers combine to total about 2 to about 50% byweight of the coating layer, more preferably about 2.5% to about 20% byweight of the coating layer on the coated MPH - ion exchange resincomplex. Preferably a plasticizer is in a range of about 2.5 to about15% by weight of the coating layer based on the coated complex providesthe most desirable properties. Suitable plasticizers may be watersoluble and water insoluble. Examples of suitable plasticizers include,e.g., dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinylalcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributylcitrate, tributyl citrate, triacetin, and Soluphor® P (2-pyrrolidone),and mixtures thereof. Other plasticizers are described in U.S. Pat.Application Publication US 2003/0099711 A1, May 29, 2003, page 4 (0041)the disclosure of which is incorporated herein by reference.

A commercial polyvinylacetate blend contains primarily apolyvinylacetate polymer, a stabilizer, and minor amounts of asurfactant such as sodium lauryl sulfate. Where the barrier coatingcomprises PVP as the stabilizer component, the final barrier coatinglayer generally contains about 5 to about 10% w/w of polyvinylpyrrolidone. In one desired embodiment, the aqueous based barriercoating solution is KOLLICOAT® SR 30 D (BASF Corporation) and whosecomposition is about 27% PVA polymer, about 2.7% polyvinylpyrrolidone(PVP), about 0.3% sodium lauryl sulfate (solids content 30%w/w), mixedwith a plasticizer. See, also, U.S. Pat. 6,066,334 and U.S. Pat.6,026,277, which is incorporated by reference herein. The PVP andsurfactant help stabilize the aqueous dispersion of the PVA. Generally,such stabilizing components are present in an amount totaling less thanabout 10% w/w, and preferably less than about 5% w/w. Optionally, aselected surfactant is present in an amount of about 1% or less. In oneembodiment, the surfactant is a non-ionic surfactant. Optionally, anionic surfactant may be selected.

In a particularly desirable embodiment, the desired modified release isobtained when the coating layer formed by application of the aqueousdispersion containing the KOLLICOAT® SR-30D - plasticizer is dried andcured. Preferably, the coating is cured for about 1 to about 24 hours.In alternate embodiments, the coating is cured for about 4 to about 16hours, and preferably about 5 hours at high temperature, e.g., about 50°C. to about 65° C., and preferably about 60° C. Thus, in one embodiment,the coated MPH - cation exchange resin complex - matrix has a curedwater-permeable, high tensile strength, water insoluble, barrier coatingcomprising a non-ionic polymer and a plasticizer and having anelongation factor in the range of about 150% to 400% over the MPH -cation exchange resin complex -matrix. In one embodiment, the barriercoating comprises a polyvinylacetate polymer, a stabilizer, a surfactantand a plasticizer. In one embodiment, a barrier coating comprises about2.5 to about 15% of plasticizer, about 70 to about 90% polyvinylacetate,about 5 to about 10% polyvinylpyrrolidone, and about 0.1 to about 1%surfactant. See, e.g., Mehta et al, U.S. Pat. Application No. US2007-0215511A, published Sep. 20, 2007, and its counterpart application,WO 2007/109104, which are incorporated herein by reference.

It may be possible to select other aqueous or non-aqueous solvent basedsystems which do not require curing. For example, an aqueous basedacrylic polymer (a Eudragit® RL30D and Eudragit® RS30D blend isdescribed herein), but requires the addition of anti-tacking agent suchas, e.g., talc or glycerol monostearate (GMS), in order to facilitateprocessing and even coating.

In one embodiment, the coating may be a EUDRAGIT® brand acrylate basedcoating materials [including, e.g., a poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) polymersystem]. For example, Eudragit® RS 30D [a pH-independent, 30% aqueousdispersion of poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1)],or Eudragit® RL 30D [a 30% aqueous dispersion, pH independent polymer,poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethylmethacrylate chloride) 1:2:0.2)] may be selected as the barrier coating.In one embodiment, a blend of Eudragit® RS 30D and Eudragit® RL 30D maybe prepared to optimize the hydrophilicity/hydrophobicity of the film inorder to achieve desirable release profiles. Suitably, a plasticizer maybe included in the coating composition. In one embodiment, the barriercoating comprises about 2.5 to about 15% of plasticizer. Individual or acombination of hydrophilic or lipophilic plasticizers with a dispersionor suspension containing the barrier coating polymer. Such plasticizersinclude, e.g., propylene glycol, polyethylene glycol, triacetin,triethyl citrate, dibutyl sebacate, vegetable oil, lipids, etc.Optionally, a suitable anti-tacking agent may be mixed with one of theEudragit® products to improve flow during coating and to address issuesof tackiness of the product during processing. Suitable anti-tackingagents include, e.g., talc, glycerol monostearate (GMS), and mixturesthereof. Suitably, these agents are present in an amount of about 0.2% -4.5% w/w based on the dry weight of the coating polymer applied to formthe coating layer of the sustained release component. Typically, thecoating layer resulting from application of the blend described in thisparagraph is not subject to any curing.

Optionally, another barrier coating may be selected. In anotherembodiment, non-aqueous solvent-based ethylcellulose such as incommercially available as the line of ETHOCEL® products by Dow] may bemodified in order to achieve the barrier coating characteristics definedherein, e.g., by addition of a sufficient amount of plasticizer toimprove flexibility and/or by curing to a sufficient temperature toachieve the desired release rate. Dow’s web site describes three ofthese products, Std 7 (viscosity of 6 - 8 mPa-s (CP); Std 10 (9-11 mPa-s(CP); Std 20 (18-22 mPa-S), each of which has a 48.0 - 49.5% ethoxylcontent) as being useful for tablet coating. Further, optionallycombining one of these polymers in combination with a water-solubleactive and/or water-soluble excipient such as a METHOCEL® celluloseether and/or CARBOWAX® polyethylene glycols is further described.Alternatively, it may be possible to modify an aqueous basedethylcellulose barrier coating in order to achieve the extended releasebarrier coating characteristics required herein, e.g., by addition of asufficient amount of plasticizer to improve flexibility and/or by curingto a sufficient temperature to achieve the desired release rate. See,e.g., the barrier coatings described in Kolter et al, U.S. Pat.6,066,334 and U.S. Pat. 6,046,277 and See, also, e.g., Wen, U.S. Pat.Nos. 6,046,277 and 6,001,392; Meadows, U.S. Published Pat. ApplicationNo. 2003/0099711 and related application WO 03/020242; SovereignPharmaceuticals, WO 2006/022996 and related applications U.S. PublishedPat. Application Nos. US2005/0232986; US2005/0232987; US2005/0232993;US2005/0266032; Bess, et al, U.S. Pat. 7,067,116; Goede et al, US PatentNo. 6,667,058, Wen et al, US Patent 6,001,392, among others.

A coating as described herein may be applied using techniques describedby the polymer manufacturer and/or techniques which are known to thoseof skill in the art. Suitable methods and apparatus have been describedin the patent and non-patent literature and include, e.g., spraying in afluid bed processor. The coating solution can be sprayed in a fluid bedprocessor (e.g., VECTOR® FLM-1 fluid bed processor) using Wursterprocess. The Coated MPH Resin Complex is then dried and/or cured. Thedried, optionally cured, coated methylphenidate - ion exchange resincomplex -optional matrix may be passed through a suitable screen inorder to ensure that the particle size is in the desired range, e.g.,capable of passing through a standard 40 mesh screen. In one embodiment,the dried, optionally cured, coated MPH ion exchange resin complex(optional matrix) granules have a mean particle size in the range ofabout 100 microns to about 450 microns, or about 150 to about 300microns.

Finished Dose Formulations

The invention provides MPH extended release chewable tablets. In orderto prepare the finished dose form, the three MPH components are blendedwith excipients and compressed into a chewable tablet. In oneembodiment, the excipients do not provide the extended releaseproperties of the chewable tablet. The sustained release profile isprovided by the sustained release barrier coated MPH - ion exchangeresin complex - matrix component.

The three MPH components may be pre-blended in the desired ratio to oneanother prior to being admixed with the excipients, described below.Alternatively, each of the three MPH components are added separately andblended with the excipients.

As described above in this specification, the sustained release barriercoated MPH -ion exchange resin complex, optionally in a matrix ispresent in an amount of about 50% w/w to about 90% w/w, about 60% w/w toabout 80% w/w, or about 65% w/w to about 75% w/w of the MPH componentsin the chewable tablet. Thus, the two immediate release componentscombine to provide about 10% w/w to about 50% w/w, about 20% w/w toabout 40% w/w, or about 25% w/w to about 35% w/w of the MPH in thechewable tablet. The uncoated MPH - ion exchange resin complex componentis designed to be immediate release as defined herein, and as such, doesnot contain a coating which functions to slow down release (e.g., nofunctional amount of an extended release barrier coating or entericcoat). Suitably, the slower onset immediate release MPH - ion exchangeresin complex supplies about 5% w/w to about 25% w/w, or about 10%w/w toabout 20% w/w, of the MPH in the chewable tablet. The extended releasecomponent and the immediate release uncoated MPH-ion exchange resincomplex are further in combination with an uncomplexed MPH drug. Thefaster onset immediate release uncomplexed MPH drug is present in anamount of about 5% w/w to about 30% w/w, or about 10% w/w to about 20%w/w, of the MPH in the chewable tablet. When the two immediate releasecomponents are expressed as a ratio, the ratio of MPH in the uncoatedMPH- resin complex (optional matrix) to uncomplexed MPH in the chewabletablet is generally in the range of about 6:1 (uncoated MPH - ionexchange resin complex: uncomplexed MPH) to about 1:6 (uncoated MPH -ion exchange resin complex: uncomplexed MPH), or about 2:1 to about 1:2.In one embodiment, the ratio of MPH from the extended release coatedMPH - ion exchange resin complex to MPH from the uncoated MPH immediaterelease component is in the range of about 18:1 (coated MPH : uncoatedMPH - ion exchange resin complex (optional matrix)) to about 5:3(coated: uncoated), or about 8:1 to about 3:1.

In one example of a chewable tablet of the invention, a methylphenidateextended release chewable tablet has a pharmacokinetic profile in whichAUC_(0-∞) for methylphenidate has a geometric mean of about 110 ng-hr/mLto about 140 ng-hr/mL, a geometric mean C_(max) of about 10 ng/mL toabout 15 ng/mL, T_(max) of about 4 hours to about 5.25 hours and T_(½)of about 5 hours to about 7 hours following a single oral administrationof an extended release chewable tablet at a dose equivalent to 40 mgracemic MPH HCl in adults.

In another example, the methylphenidate chewable tablet has apharmacokinetic profile in which AUC_(0-∞) for methylphenidate has ageometric mean of about 113 ng-hr/mL under fasted conditions and about138 ng-hr/mL under fed conditions, a geometric mean C_(max) of about 12ng/mL to about 13 ng/mL under fasted and fed conditions, an arithmeticmean T_(max) of about 4 to about 4.5 hours under fasted and fedconditions and an arithmetic mean T_(½) of about 5.2 hours under fastedand fed conditions, following a single oral administration of anextended release chewable tablet at a dose equivalent to 40 mg racemicMPH HCl in adults. For example, the extended release chewable tablet mayhave the pharmacokinetic profile of FIG. 1 following a single oraladministration at a dose equivalent to 40 mg racemic MPH HCl in adults.

The MPH extended release chewable tablets may be prepared using one ormore of a filler, one or more disintegrant, one or more binder, one ormore a buffering agent, one or more lubricant, one or more glidant, orblends of these components. Suitably, the tablets also include tasteand/or mouth feel enhancers including, e.g., one or more of a sweetener,a flavorant, a gum, or blends of these components. Optionally, thetablet may also contain a non-functional coating.

As used herein, a “non-functional coating” refers to a coating whichcontributes no detectable modified release functions. The non-functionalcoating may be a polymer may serve as a moisture barrier to preserve theintegrity of the tablet during storage or to facilitate application of acolor coating layer. Additionally or alternatively, the non-functionalcoating may provide a color coating layer or improve the “smoothness” ormouth feel of the tablet. In one embodiment, the non-functional coatingmay increase the hardness of the tablet somewhat without affecting thechewability thereof.

Throughout the specification, where weight percentages of excipients andthe three active components are provided, the weight percentages areexclusive of any weight added by a non-functional coating. Weightpercentages of these non-functional coatings, where present, areprovided as weight added, in an amount of about 1% to about 20%, orabout 2% to about 10%, or about 3% to about 5% weight added to thefinished chewable tablet.

Typically, a chewable tablet will contain a filler or a mixture offillers in the range of about 10% w/w to about 90% w/w, about 50% w/w toabout 85% w/w, or about 50% w/w to about 70% w/w of the total tabletweight. Suitable fillers may include, e.g., Mannitol, Lactose, Maltose,Fructose, Sucrose, Xylitol, Maltitol, Microcrystalline Cellulose,Dicalcium phosphate, Guargum, Xanthan gum, Tragacanth gum,Pre-gelatinized Starch, Compressible sugar, Calcium carbonate, Magnesiumcarbonate, Calcium sulfate, Dextrates, Maltodextrin. In one embodiment,a chewable tablet of the invention contains a blend of mannitol, xanthangum, microcrystalline cellulose, and guargum in an amount of about 60%w/w to about 75% w/w. In one embodiment, a gum or a combination of gumsis provided in an amount of about 0.25% w/w to about 5% w/w, or about0.25% to about 1% w/w. In another embodiment, microcrystalline celluloseis provided in an amount of about 5% w/w to about 25% w/w, or about 10%w/w to about 15% w/w based on the total tablet weight prior to anynon-functional coating. A product containing a combination ofmicrocrystalline cellulose and guar gum is commercially available asAvicel ®, which contains a ratio of 80 parts by weight microcrystallinecellulose to 20 parts by weight guar gum. This blend of microcrystallinecellulose (MCC) and guar gum may be present in an amount of about 5% w/wto about 25% w/w of the total tablet weight.

A chewable tablet as described herein will also contain a disintegrantor blend of disintegrants in the range of about 1% w/w to about 15% w/w,or about 5% w/w to about 10% w/w, or about 7% w/w to about 8% w/w basedon the total tablet weight. Suitable disintegrants include, e.g.,Crospovidone, Sodium starch glycolate, Croscarmellose sodium,Carboxymethyl cellulose sodium, Carboxymethylcellulose calcium, Starch.In one embodiment, a tablet as described herein contains crospovidone ina range of about 5% w/w to about 10% w/w. or about 7.5% w/w based on thetablet weight prior to any non-functional coating being applied.

The binder for the chewable tablet may be absent (i.e., 0%), oroptionally, present in an amount of about 1% w/w to about 15% w/w of thetotal tablet weight. Examples of suitable binders includepolyvinylpyrrolidone (Povidone), Hydroxypropyl methyl cellulose,Hydroxypropyl cellulose, Hydroxyethyl cellulose, Hydroxyethyl cellulose,Methyl cellulose, Polyvinyl alcohol, Starch, Acacia, Alginic acid,Sodium alginate.

In one embodiment, the chewable tablet of the invention contains asweetener in an amount of about 0.01% w/w to about 3% w/w, or about 0.5%w/w to about 2% w/w, or about 1% w/w to about 2% w/w or about 1.5% w/w,based on the total tablet weight exclusive of any optionalnon-functional coating. Suitable sweeteners may include, e.g.,Aspartame, Saccharin, Saccharin sodium, Sucralose, Sodium cyclamate,Xylitol, Acesulfame Potassium, and blends thereof. Optionally, inaddition to functioning as a sweetener, an excipient may function as afiller. Examples of suitable sweeteners/fillers including, e.g.,fructose, sucrose, xylitol, maltitol. Optionally, when performing bothfunctions, the excipient may be present in an amount in excess of about10% w/w of the tablet. In such an instance, additional sweetener may beomitted (e.g., present in 0% added sweetener). Alternatively, a secondsweetener or a combination of sweeteners which differs from the filleris added in the amount provided in this paragraph in order to furtherenhance taste.

Suitably, the tablet is provided with a buffering agent in an amount ofabout 0.1% w/w to about 5% w/w, or about 0.5% w/w to about 1.5% w/wbased on the total tablet weight. Examples of suitable buffering agentsinclude, e.g., citric acid, tartaric acid, malic acid, lactic acid, andacceptable salts thereof, and mixtures thereof. In one embodiment, thebuffering agent adjust the pH of the tablet (if suspended in water) to arange of about 3.5 to about 5, or about 4 to about 4.5. In oneembodiment, the buffering agent is citric acid, which also providesdesirable taste properties.

When an additional flavoring agent is added, the flavoring agent(s) maybe added in an amount of about 0.05% w/w to about 3% w/w, or about 0.1%to about 1% w/w or about 0.5% w/w, based on the total weight of thetablet (exclusive of any optional non-functional coating). Suitableflavoring agents may include, both natural and artificial flavoringagents such as are generally available through several custommanufacturers around the world such as Fona [Illinois, US], Givaudan(Vernier, Switzerland), Ungerer & Company (Lincoln Park, N.J.), andInternational Flavors & Fragrances (New York, N.Y.) to name a few. Thoseskilled in the art will recognize that there are several commercialsources available including custom blenders. The flavorings may beblended prior to addition to the pharmaceutical composition or addedseparately. Still other flavoring agents such as cherry, strawberry,vanilla, grape, banana and other flavors or mixtures thereof may beselected.

Optionally, a colorant may be provided to the tablet to provide adesired visual appeal or trade dress. Such colorants may be added in therange of about 0.001 to about 1% w/w, or about 0.01% w/w to about 0.08%w/w or about 0.05% w/w, based on the total weight of the tablet(exclusive of any non-functional coating). Such colorants are availablefrom a variety of sources including, e.g., Colorcon, Noveon, andSpectra.

In order to facilitate production of the chewable tablet, excipientssuch as lubricants and glidants may be utilized. A lubricant may beutilized in an amount of about 0.1% w/w to about 5% w/w, about 0.2% w/wto about 4.5% w/w, or about 1.5% w/w to about 3% w/w of the total weightof the tablet. Examples of lubricants may include, e.g., Talc, MagnesiumStearate, sodium stearyl fumarate, Stearic acid, Zinc Stearate, CalciumStearate, Magnesium trisilicate, Polyethylene glycol, and blendsthereof. In one embodiment, talc and magnesium stearate are used intablet preparation. The resulting tablet may contain about 0.1% w/w toabout 3% w/w talc and about 0.5% w/w to about 0.5% w/w magnesiumstearate. A glidant may be used in an amount of about 0.01% w/w to about0.5% w/w, or about 0.1% w/w to about 0.3% w/w, based on the total weightof the tablet. Examples of suitable glidants include, e.g., silicondioxide and tribasic calcium phosphate. In one embodiment, the glidantis silicon dioxide which is used in an amount of about 0.001% w/w toabout 0.1% w/w or about 0.05% w/w.

Optionally, other excipients may be selected from conventionalpharmaceutically acceptable carriers or excipients and well establishedtechniques. Without being limited thereto, such conventional carriers orexcipients include diluents, binders and adhesives (i.e., cellulosederivatives and acrylic derivatives), lubricants (i.e., magnesium orcalcium stearate, or vegetable oils, polyethylene glycols, talc, sodiumlauryl sulfate, polyoxy ethylene monostearate), thickeners,solubilizers, humectants, disintegrants, colorants, flavorings,stabilizing agents, sweeteners, and miscellaneous materials such asbuffers and adsorbents in order to prepare a particular pharmaceuticalcomposition. The stabilizing agents may include preservatives andanti-oxidants, amongst other components which will be readily apparentto one of ordinary skill in the art.

The following Table provides exemplary formulations of MPH extendedrelease chewable tablets according to the invention, based on the totalweight of the tablet.

Component Broad Range w/w Narrower Range Coated MPH - ion exchange resincomplex (coated MPH polistirex) 15%-20% 16%-18% Uncoated MPH polistirex1.5%-3.5% 2%-3% Uncomplexed MPH 0.5%-0.9% 0.6%-0.8% Filler(s) 45%-85%50%-70% Mannitol 40%-60% 45%-55% Xanthan Gum 0.1%-1% 0.25%-0.75% MCC +guar gum 5%-25% 10%-20% Disintegrant(s) 5%-10% 7%-8% Binder(s) 0%-8%2%-6% Sweetener(s) 0.5%-3% 1%-2% Buffering Agent 0.1%-5% 0.5%-1.5%Flavoring Agent 0.1%-3% 0.1%-1% Lubricant(s) 0.2%-4.5% 1.5%-3% Talc0.1%-3% 1%-2% Magnesium stearate 0.1%-1.5% 0.5%-1% Glidant 0.01%-1%0.1%-0.3% Colorant 0.01%-0.5% 0.02%-0.08%

Suitably, a chewable tablet of the invention is prepared as a singleuniform solid dispersion. A typical manufacturing process for making achewable tablet generally involves blending of the desired ingredientsto form a uniform distribution of the coated MPH - ion exchange resincomplex, the uncoated MPH - ion exchange complex, the uncomplexed MPH,and the excipients. If desired, a blend of the three MPH components maybe formed prior to blending into the excipient. The blend is thencompressed into a single layer using standard methods and tablet pressessuch as well-known to those skilled in the art (e.g., Kilian, Fette,Kirsch, Elizabeth, Sejong, Kikisui, SMI, Colton, Stok, and Manesty,amongst others.)

The working examples below describe forming a chewable tablet of theinvention into a capsule shape, optionally with a single bisect (asingle scoring at the mid-line which facilitates splitting the tabletinto halves). However, other shapes may be readily selected, including,e.g., a standard round shape, a flat faced shape, oval, bullet, square,triangle, diamond, pentagon, octagon, amongst others. Optionally, one ormore of these tablet shapes may be provided with a quadrisect, i.e., twoperpendicular scores which facilitate splitting the tablet intoquarters.

Optionally, the tablet may have one or more sealant or top coating whichdoes not function to modify or extend release but which providesmoisture barrier, of a color coating or other visual appeal. Forexample, such a coating may provide a “shine” to the tablet, enhancepalatability, serve as an identifying color for the tablet, or otherpurposes. Such coatings are available commercially, e.g., from Colorconor other suppliers. Typically, such a coating is composed ofhydroxypropylmethylcellulose (HPMC) or polyvinylalcohol and is presentin an amount of about 1% w/w to about 20% w/w, or about 2% w/w to about10% w/w of the total tablet weight.

The finished tablets may be stored in glass or high density polyethylene(HDPE) bottles with or without a heat induced sealed (HIS) bottle. Thebottle may also contain a dessicant. Alternatively, the tablets may beencapsulated into blister packs using standard methods well-known tothose skilled in the art.

An MPH extended release chewable tablet of the invention may be orallyadministered to a patient having a disorder treatable by MPH. Theseinclude disorders for which regulatory approval has been granted in theUS or other jurisdiction in which the drug is being administered andwhich requires regulatory approval. For example, MPH is currentlyapproved for treatment of Attention Deficit Hyperactivity Disorder(ADHD), postural orthostatic tachycardia syndrome, and narcolepsy. MPHhas also been described in patent applications and in the literature asbeing useful for treatment of such disorders including, but are notlimited to, behavioral disorders, treatment-resistant cases of lethargy,depression, neural insult, obesity, and rarely other psychiatricdisorders such as obsessive-compulsive disorder, Attention DeficitDisorder, specific dyslexias, brain dysfunction, cognitive decline inAIDS and AIDS related conditions, alertness in geriatric, Alzheimer’spatients and recovering stroke victims.

Thus, the invention provides a method of treating one or more of theabove disorders for a period of at least twelve hours by administering aMPH extended release chewable tablet containing a blend of a barriercoated methylphenidate - ion exchange resin complex -matrix, a first MPHimmediate release component (e.g., an uncoated MPH - ion exchange resincomplex), and a second MPH immediate release component (uncomplexedMPH).

A composition of the invention is formulated to deliver MPH is, mostdesirably, in dosages ranging from about 1 mg up to about 100 mg perday, preferably from about 10 to about 75 mg per day, or in about 25 or60 mg doses [based on equivalence to racemic methylphenidate HCl]although variations will necessarily occur depending upon the weight andcondition of the subject being treated and the particular route ofadministration chosen. Actual dosages of dexmethylphenidate may be athalf the amounts of racemic methylphenidate. Variations may neverthelessoccur depending upon the weight and condition of the persons beingtreated and their individual responses to said medicament.

As described herein, the MPH extended release chewable tablets of theinvention can be dosed orally twice-a-day at 12-hour intervals. However,depending upon the patient, smaller doses may be delivered at intervalsduring the day. Other patients may take a single dose in the morning andforego dosage in the evening.

An in vitro dissolution test determines whether chewable tabletsdisintegrate within a prescribed time when placed in a dissolution mediaunder prescribed experimental conditions. Disintegration is defined asthe state in which no residue of the tablet, except fragments ofundissolved coating, remains on the screen of the test apparatus or, ifany other residue remains, it consists of a soft mass having no palpablyfirm, unmoistened core.

Suitable methods for in vitro testing of chewable tablet dissolutionhave been described, e.g., by the World Health Organization (WHO)International Pharmacopoeia,(http://www.who.int/medicines/publications/pharmacopoeia/). An exampleof a suitable disintegration apparatus is described as follows. Theapparatus consists of a circular basket-rack assembly, a suitable vesselfor the immersion fluid (such as a 1-litre beaker), a thermostaticarrangement for maintaining the fluid at the required temperature(normally 37 ± 2° C.), and a device for raising and lowering thebasket-rack in the immersion fluid at a constant frequency of 28-32cycles/min through a distance of 50-60 mm. The basket-rack assemblyconsists of six open-ended cylindrical glass tubes and a rack forholding them in a vertical position. The tubes are 75-80 mm long, andhave an inside diameter of about 21.5 mm and a wall about 2 mm thick.The tubes are held vertically by two superimposed plates, circular inshape and made of transparent plastic material, each about 90 mm indiameter and 6 mm thick, perforated by six holes of a diameter thatallows the tubes to be inserted. The holes are equidistant from thecenter of the plate and equally spaced one from another. A piece ofwoven gauze, made of stainless steel wire about 0.635 mm in diameter,with a mesh aperture of 2.0 mm is attached to the underside of the lowerplate. The upper plastic plate is covered with a stainless steel plate,about 1 mm thick, of a diameter similar to that of the plastic plates.The steel plate is perforated by six holes about 22 mm in diameter,positioned to coincide with those of the upper plastic plate. It isplaced over the tubes and consolidates the whole structure. The platesare held rigidly 75-80 mm apart by vertical stainless steel rods at theperiphery. A metal rod is fixed to the center of the upper plate. Thisenables the assembly to be attached to a suitable mechanical device sothat it may be lowered and raised. The volume of the fluid in theimmersion vessel should be such that, at the highest point of the upwardstroke, the wire mesh that forms the bottom of the basket remains atleast 25 mm below the surface of the fluid. At the lowest point of thedownward stroke, it should descend to not less than 25 mm from thebottom of the vessel. The time required for the upward stroke should beequal to the time required for the downward stroke, and the change instroke direction should be a smooth transition rather than an abruptreversal of motion. Where a disc is prescribed in the monograph, thefollowing configuration and dimensions apply: a cylindrical disc 20.7 ±0.15 mm in diameter and 9.5 ± 0.15 mm thick, made of transparent plasticwith a relative density of 1.18 to 1.20. Each disc is pierced by fiveholes 2 mm in diameter, one in the center and the other four spacedequally on a circle of radius 6 mm from the center of the disc. On thelateral surface of the disc, four equally spaced grooves are cut so thaton the upper surface of the disc they are 9.5 mm wide and 2.55 mm deepand, at the lower surface, 1.6 mm square. Different designs ofbasket-rack assembly may be used, provided that the specifications forthe glass tubes and the stainless steel wire gauze are maintained. Invitro dissolution of the methylphenidate chewable tablet of theinvention may be assessed through a variety of methods including, e.g.,Food and Drug Administration (FDA) - accepted dissolution tests,including the Basket Method (I) approved for use with a methylphenidatechewable tablet,http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm,have been described. The current FDA-approved dissolution test for aprior art methylphenidate chewable tablet utilizes water and a paddlespeed of 100 rpm, at 900 mL, with testing at 15, 30, 45 and 60 minutes.Other methylphenidate tablets have different dissolution tests anddifferent media. However, since the barrier coated methylphenidate -ionexchange complex described herein is not readily soluble in water, thepreviously described tests are dissolution medium is not suitable fortesting dissolution of the present tablets at those time frames.Accordingly, a dissolution medium of phosphate buffer is utilized in theworking examples below to assess in vitro dissolution of the MPHextended release chewable tablets described herein of the inventionrather than water.

Suitably, the MPH extended release tablet of the invention can be scoredwithout affecting the extended release profile. Thus, the oral dose isreadily titrated, i.e., split in half, in order to readily andaccurately deliver half the dose of the finished tablet.

EXAMPLES

The following examples are illustrative only and are not intended to bea limitation on the present invention.

Example 1: Methylphenidate (MPH) Extended Release (ER) Chewable Tablets(CT) Prepared Using a Blend of Eudragit® RS 30D and Eudragit® RL 30DPolymer as Barrier Coating for Sustained Release Component

In the below example the Finished product, MPH ERCT - 20 mg contains 70%of the dose as Coated (Eudragit® RS 30D and Eudragit® RL 30D) MPHPolistirex Matrix, 15% of dose as Uncoated MPH Polistirex and 15% of thedose as MPH HCl.

A. Coated Methylphenidate Polistirex

Ingredients Quantity Uncoated Methylphenidate-Ion exchange resin complex(Uncoated MPH Polistirex) Methylphenidate (MPH) HCl (Covidien) 3100 gSodium Polystyrene Sulfonate Amberlite® IRP69 ion exchange resin [RohmHaas] 7693 g Purified Water* Qs* Pre-Coated MPH Polistirex Uncoated MPHPolistirex 8500 g Povidone [Kollidon® K30, BASF] 657 g Purified water*2629 g Purified Water* Qs* Coated MPH Polistirex Pre-coated MPHPolistirex - (Povidone) Matrix 600 g Poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2[Eudragit® RL30D dispersion**, Evonik] 75.26 g Poly(ethylacrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylatechloride) 1:2:0.1 [Eudragit® RS30D dispersion**, Evonik] 376.3 gTriethyl Citrate 27.0 g Talc 33.87 g Purified Water* 694.56 g *Removedduring processing ** 30% w/w aqueous dispersion

1. Uncoated Methylphenidate Polistirex

The MPH - ion exchange resin complex (MPH polistirex), was prepared byfirst adding 80 L of Purified Water into a PEF 450 PallSchenk vessel anddissolving methylphenidate HCl by continuous mixing. Sodium PolystyreneSulfonate ion exchange resin [Amberlite® IRP69, Rohm &Haas] wasdispersed with continuous mixing and the mixing was continued for 60minutes. Water was removed by filtration process followed by rinsingtwice using purified water (40 L). Wet resin complex was then drieduntil moisture content was between 3-7%. Dried MPH - ion exchange resincomplex was passed through a 40 mesh screen using the CO-MIL® device.This was the Uncoated MPH Polistirex.

In a separate container Povidone (polyvinylpyrrolidone) was dissolved in2629 gms of Purified Water (Povidone solution). Uncoated MPH Polistirexprepared as described earlier in this example was treated with Povidonesolution with continuous mixing to form a uniform mass of uncoated MPHpolistirex in a matrix with the povidone. The uncoated MPH polistirex -matrix was dried until the moisture content was between 15-25%.Semi-dried MPH polistirex - matrix was then milled using CO-MIL® brandmill fitted with 40 mesh screen. Milled MPH polistirex - matrix wasfurther dried until moisture content was between 3-7%. Dried MPHpolistirex - matrix was passed through a CO-MIL® fitted with 40 meshscreen. This was the Pre-Coated MPH Polistirex - Matrix.

The Coated MPH Polistirex - Matrix was prepared as follows. The coatingsolution was prepared by mixing Purified water and Triethyl Citrate in acontainer and later Talc was dispersed using high shear mixer for 10minutes (Talc dispersion). In a separate container Eudragit® RS 30D andEudragit® RL 30D were added and mixed with Talc dispersion for 45minutes. The coating process was performed in a fluid bed processorequipped with Wurster column by applying coating solution on toPre-coated MPH Polistirex - Matrix that resulted in 30% weight gain. TheCoated MPH Polistirex - Matrix was again passed through Sieve No. 40mesh screen.

B. Methylphenidate ER Chewable Tablets

Ingredients qty/batch (g) Coated MPH Polistirex - (Povidone) Matrix fromPart A 60.45 Uncoated MPH Polistirex from Part A 8.01 MPH HCl 2.25Mannitol 145.44 Xanthan gum 1.5 Crospovidone 22.5 MicrocrystallineCellulose and Guar gum [Avicel® FMC Biopolymer, 80:20 weight ratio ofMCC to guar gum] 45 Aspartame 4.5 Citric acid 3 Flavor 1.5 Talc 3Silicon dioxide 0.6 Magnesium stearate 2.25

Mannitol and Microcrystalline Cellulose and Guargum were screenedthrough 20 mesh screen and loaded into the cube blender. Coated MPHPolistirex - Matrix prepared as in the previous section, Uncoated MPHPolistirex, MPH HCl, Xanthan gum, Crospovidone, Aspartame, Citric acid,Flavor, Talc, Silicon dioxide were screened through 40 mesh screen andloaded into the cube blender and mixed for 10 minutes. MagnesiumStearate was screened through 40 mesh screen and loaded into the blenderand mixed for additional 5 minutes. The powder blend was compressed on a10 station rotary tablet press using 0.2625 X 0.5720 capsule shapedtooling. The final weight of the compressed tablet was 400 mg.

Example 2: Methylphenidate ER Chewable Tablets Prepared Using a CuredPolyvinylacetate - Plasticizer Barrier Coating for Sustained ReleaseComponent

In the below example the Finished product, MPH ERCT - 40 mg contains 70%of the dose as Coated (Kollicoat SR 30D) MPH Polistirex - Matrix, 15% ofdose as Uncoated MPH Polistirex and 15% of the dose as MPH HCl.

A. Coated Methylphenidate Polistirex

Ingredients Quantity Uncoated Methylphenidate Polistirex MPH HCl 15500 gSodium Polystyrene Sulfonate Amberlite® IRP69 ion exchange resin 38450 gPurified Water* Qs* Pre-Coated MPH Polistirex Uncoated MPH Polistirex40000 g Povidone (Kollidon® K30; BASF) 3092 g Purified water* 12372 gPurified Water* Qs* Coated MPH Polistirex Pre-coated MPH Polistirex -(Povidone) Matrix 34000 g Polyvinyl Acetate Dispersion** (Kollicoat®SR30D, BASF) 34300 g Triacetin 513 g Purified Water* 19200 g *Removedduring processing ** 30% w/w aqueous dispersion

The MPH - ion exchange resin complex (MPH polistirex) was prepared byfirst adding 400 L of Purified Water in to a large scale multi-purposevessel and MPH HCl was dissolved by continuous mixing. SodiumPolystyrene Sulfonate ion exchange resin was dispersed with continuousmixing and the mixing was continued for 60 minutes. Water was removed byfiltration process followed by rinsing twice using purified water. WetMPH polistirex was then dried until the moisture content was between3-7%. Dried MPH polistirex was passed through a 40 mesh screen using theCO-MIL®. This was the Uncoated MPH Polistirex.

In a separate container Povidone was dissolved in 12372 gms of PurifiedWater (Povidone solution). Uncoated MPH Polistirex was treated withPovidone solution with continuous mixing to form a uniform mass toprovide an uncoated MPH polistirex in a matrix with the povidone. Wetmass was dried until the moisture content was between 15-25 %.Semi-dried uncoated MPH polistirex - (povidone) matrix was then milledusing CO-MIL® fitted with a 40 mesh screen. Milled material was furtherdried until moisture content was between 3-7%. Dried uncoated MPHpolistirex - (povidone) matrix was passed through a CO-MIL® fitted with40 mesh screen. This was the Pre-Coated MPH Polistirex -(povidone)matrix.

The Coated MPH Polistirex - Matrix was prepared as follows. The coatingsolution was prepared by mixing Triacetin, Purified Water and PolyvinylAcetate dispersion in a separate container. The coating process wasperformed in a fluid bed processor equipped with Wurster column byapplying coating solution on to Pre-coated MPH Polistirex that resultedin 30% weight gain. The Coated MPH Polistirex - Matrix was placed in thehot air oven at 60° C. for 5 hours. The Coated MPH Polistirex - Matrixwas again passed through Sieve No. 40 mesh screen. This was the cured,coated MPH Polistirex -Matrix.

B. Methylphenidate ER Chewable Tablets

Ingredients quantity/batch (g) Cured, Coated MPH Polistirex - Matrixfrom Example 2 Part A 16576 Uncoated MPH Polistirex from Example 2 PartA 2534 MPH HCl 720 Mannitol 48810 Xanthan gum 480 Crospovidone 7200Microcrystalline Cellulose and Guar gum [Avicel® FMC Biopolymer; 80:20MCC to guar gum ratio by weight] 14400 Aspartame 1440 Citric acid 960Flavor 480 Colorant 48 Talc 1440 Silicon dioxide 192 Magnesium Stearate720

Mannitol and Microcrystalline Cellulose and Guargum were screenedthrough 20 mesh screen and loaded into the ‘V’ blender. Cured, coatedMPH Polistirex - Matrix, Uncoated MPH Polistirex, MPH HCl, Xanthan gum,Crospovidone, Aspartame, Citric acid, Flavor, Talc, Silicon dioxide werescreened through 40 mesh screen, Colorant was screened through 60 meshand loaded into the ‘V’ blender and mixed for 10 minutes. MagnesiumStearate is screened through 40 mesh screen and loaded into the blenderand mixed for additional 5 minutes. The resulting powder blend wascompressed on a 36 station rotary tablet press using a 0.3310 × 0.7210capsule shaped tooling to produce a capsule shaped compressed MPHextended release (ER) chewable tablet. The final weight of thecompressed tablet was 800 mg.

C. Non-Functional Coating of MPH ER Chewable Tablet

Ingredients quantity/batch (g) Opadry® (polyvinylalcohol) 4020 Purifiedwater 36180

In a separate container Opadry® polymer was dispersed in 36180 gm ofpurified water and mixed for 45 minutes. The coating process wasperformed in a perforated coating pan by applying coating solution on tothe compressed MPH ER Chewable Tablets that resulted in 3% weight gain.

Example 3: Methylphenidate ER Chewable Tablets Prepared Using a CuredPolyvinylacetate - Plasticizer Barrier Coating for Sustained ReleaseComponent

In the below example the Finished product, MPH ERCT - 40 mg contains 80%of the dose as Coated MPH Polistirex (Kollicoat® SR 30D), 10% of dose asUncoated MPH Polistirex and 10% of the dose as MPH HCl.

A. Coated Methylphenidate Polistirex

Ingredients Quantity Uncoated MPH Polistirex Methylphenidate HCl 15500 gSodium Polystyrene Sulfonate Amberlite® IRP69 ion exchange resin [RohmHaas] 38450 g Purified Water* Qs* Pre-Coated MPH Polistirex Uncoated MPHPolistirex 30000 g Povidone (Kollidon® K30) 2319 g Purified water* 10940g Purified Water* Qs* Coated MPH Polistirex Pre-coated MPH Polistirex -(Povidone) Matrix 32000 g Polyvinyl Acetate Dispersion** (Kollicoat®SR30D, BASF) 32300 g Triacetin 483 g Purified Water* 18100 g *Removedduring processing ** 30% w/w aqueous dispersion

A MPH - ion exchange resin complex (MPH Polistirex) was prepared byfirst adding 400 L of Purified Water in to the vessel and dissolvingmethylphenidate HCl by continuous mixing. Sodium Polystyrene Sulfonateion exchange resin was dispersed with continuous mixing and the mixingwas continued for 60 minutes. Water was removed by filtration processfollowed by rinsing twice using purified water. Wet MPH polistirex wasthen dried until moisture content was between 3-7%. Dried MPH polistirexwas passed through a 40 mesh screen using the CO-MIL® brand mill. Thiswas the Uncoated MPH Polistirex.

In a separate container Povidone was dissolved in 10940 gms of PurifiedWater (Povidone solution). Uncoated MPH Polistirex complex was treatedwith Povidone solution with continuous mixing to form a uniform masswhich resulted in the formation of a matrix between the uncoated MPHpolistirex and povidone. The wet mass containing the uncoated MPHpolistirex - matrix was dried until the moisture content was between15-25 %. Semi-dried uncoated MPH polistirex - matrix was then milledusing CO-MIL® brand mill fitted with a 40 mesh screen. Milled uncoatedMPH polistirex - matrix was further dried until moisture content wasbetween 3-7%. Dried material was passed through a CO-MIL fitted with 40mesh screen. This was the Pre-Coated MPH Polistirex - matrix.

The Coated MPH Polistirex - Matrix was prepared as follows. The coatingsolution was prepared by mixing Triacetin, Purified Water and PolyvinylAcetate dispersion in a separate container. The coating process wasperformed in a fluid bed processor equipped with Wurster column byapplying coating solution on to Pre-coated MPH Polistirex - Matrix thatresulted in 30% weight gain. The Coated MPH Polistirex - Matrix wasplaced in the hot air oven at 60° C. for 5 hours. The cured, coated MPHPolistirex - Matrix was again passed through number 40 mesh screen. Thiswas the cured, coated MPH Polistirex - Matrix used for preparing thechewable tablet.

B. Methylphenidate ER Chewable Tablets

Ingredients quantity/batch (g) Cured, Coated MethylphenidatePolistirex - Matrix prepared according to Example 3 Part A 59.19Uncoated Methylphenidate Polistirex prepared according to Example 3 PartA 5.34 Methylphenidate Hydrochloride 1.5 Mannitol 149.97 Xanthan gum 1.5Crospovidone 22.5 Microcrystalline Cellulose and Guar gum [Avicel® FMCBiopolymer] 45 Aspartame 4.5 Citric acid 3 Flavor 1.5 Colorant 0.15 Talc3 Silicon dioxide 0.6 Magnesium Stearate 2.25

Mannitol and Microcrystalline Cellulose and Guargum were screenedthrough 20 mesh screen and loaded into the ‘V’ blender. CoatedMethylphenidate Polistirex, Uncoated Methylphenidate Polistirex,Methylphenidate Hydrochloride, Xanthan gum, Crospovidone, Aspartame,Citric acid, Flavor, Talc, Silicon dioxide were screened through 40 meshscreen, Colorant was screened through 60 mesh and loaded into the ‘V’blender and mixed for 10 minutes. Magnesium Stearate is screened through40 mesh screen and loaded into the blender and mixed for additional 5minutes. The powder blend was compressed on a 36 station rotary tabletpress using 0.3310 × 0.7210 capsule shaped tooling. The final weight ofthe compressed tablet was 800 mg.

C. Non-Functional Coating of MPH ERCT

Ingredients quantity/batch (g) Opadry® (polyvinylalcohol) 10 Purifiedwater 90

In a separate container Opadry® polyvinylalcohol non-functional coatingwas dispersed in 90 gm of purified water and mixed for 45 minutes. Thecoating process was performed in a perforated coating pan by applyingcoating solution on to the compressed MPH ER Chewable Tablets thatresulted in 3% weight gain.

The scored chewable tablet when split, is expected to show the extendedrelease profile as is characteristic of the intact tablet in vitro. Thefollowing example shows the in vitro dissolution profiles of splitversus whole tablet of the 20 mg and 30 mg methylphenidate ER chewabletablets.

Example 4: Methylphenidate Extended Release Chewable Tablet A. SplitTablet Dissolution

The tablets used in this study are the same ingredients as described inExample 2 for a 40 mg tablet, with the exception of the non-functionalcosmetic coating. In order to prepare the 20 mg tablet used in thisstudy, the same three MPH components and the same excipients asidentified in Example 2 were combined at ½ the weight percentages ofeach ingredient defined in Example 2. In order to prepare the 30 mgtablet used in this study, the same three MPH components and the sameexcipients as identified in Example 2 were combined at ¾ the weightpercentages of each ingredient identified in Example 2.

The following in vitro dissolution assessment was performed usingconventional USP testing on the whole (unscored) or split tablets placedin 900 mL 0.4 M potassium phosphate buffer (KH₂PO₄) at 37 ± 0.5° C. witha USP paddle speed of 75 rpm. This assessment was designed to show thein vitro dissolution rate over a twelve hour period.

Form % Dissolved 0.5 h 1 h 2 h 3 h 6 h 8 h 12 h 20 mg, whole tablet 4655 66 72 84 88 92 20 mg Tablet Split in Half 44 53 65 71 82 85 89 30 mg,whole tablet 46 55 67 74 85 90 94 30 mg Tablet, Split in Half 47 57 6976 89 93 97

B. Comparative Dissolution Study

In another dissolution study, the 40 mg methylphenidate ER chewabletablet, prepared as described in Example 2, was compared to MPH ERchewable tablets with the sustained release component and only one ofthe two immediate release components. Thus, 40 mg tablet was preparedwith the same excipients in Example 2, but having a combination of thecoated MPH polistirex - matrix and only the faster release MPH immediaterelease component (racemic MPH HCl). The MPH HCl is present in doublethe weight amount described in Example 2 and the slower release uncoatedMPH polistirex is absent. This is the 70/30 coated/MPH HCl tablet shownin the table below. The second comparative 40 mg tablet contains thesame excipients as in Example 2, but in contrast to Example 2, theactive components are a combination of the coated MPH polistirex -matrix and double the weight amount of the slower release MPH immediaterelease component (uncoated MPH polistirex); no MPH HCl is included inthis formulation. This is the 70/30 coated/uncoated tablet shown in thetable below.

Each of the three active components is prepared as described in Example2. Each of the tablets are prepared as described in Example 2, with theexception of the weights of the immediate release components showing thecomparative two-component tablets.

In order to enhance the ability to observe the onset of release within60 minutes, another study to monitor first hour of dissolution every 10minutes was used than that described in Example 4A for the split tabletdissolution. With the exception of the buffer strength, the in vitrodissolution assessment was performed as described in Part A above byplacing the tablets in 900 mL of the buffer at 37 ± 0.5° C. and using aUSP paddle speed of 75 rpm.

Form % Dissolved 10 min 20 min 30 min 45 min 60 min 70/30 (coated curedMPH polistirex - matrix / MPH HCl) 30 31 32 33 35 70/15/15 (coated curedMPH polistirex - matrix/uncoated MPH polistirex/MPH HCl) Tablet ofExample 2 25 28 30 32 33 70/30 (coated cured MPH polistirex -matrix/uncoated MPH polistirex) 21 25 27 29 30

The initial dissolution profiles show the order of release rate as:coated/MPH HCl > coated/uncoated/MPH HCl > coated/uncoated. Theinclusion of MPH HCl to replace a portion of uncoated showed increase inthe initial release rate.

C. Compression Pressure Dissolution Study

The chewable tablets when compressed under the pressure of 8 to 23kp,show no difference in the release profile of the methylphenidate ERchewable tablets. The dissolution study was performed as described inExample 4A. An example of the release rate of the 40 mg formula ofExample 2 is listed in the following table. These tested hardness arenot limitations on the chewable tablet, but are illustrative only.

Methylphenidate ERCT, 40 mg (70/15/15) - Hardness study % Dissolved 0.5h 1 h 2 h 3 h 6 h 8 h 12 h Comments 47 56 67 74 86 89 92 8-10 kp, LowHardness 46 55 66 74 86 90 93 14-16 kp, Normal Hardness 47 56 67 75 8790 93 20-23 kp, High Hardness

Example 5: Single Dose Pharmacokinetics of an Extended ReleaseMethylphenidate Chewable Tablet

A three-way cross-over pharmacokinetic study has been performed using(1) MPH ER chewable tablets prepared according to Example 2 of thisspecification (Test) dosed 40 mg at 0 hour under fasted condition (2)MPH ER chewable tablets prepared according to Example 2 of thisspecification (Test) dosed 40 mg under fed condition and (3) IR chewabletablets (reference) [Methylin® 10 mg chewable tablet; Shionogi Inc]dosed 20 mg at 0 and 6 hours under fasted condition.

Calories (kcal) Total fat (g) Carbohydrate (g) Protein (g) 250 mL ofwhole milk 160 8 12 8 2 slices of bacon 89 7 0 6 Total weight 56 85 36Total calories (kcal) 504 340 144 Related caloric content 50.6% 34.1%14.4%

The objective is to determine the relative bioavailability of MPH ERchewable tablets of the invention product versus reference and to alsoevaluate the food effect on the chewable tablets of the invention.

This is an open-label, single- and multi-dose, randomized, 3-period,3-sequence, 3-treatment, crossover study, designed to evaluate therelative bioavailability of two formulations of methylphenidate HClextended release chewable tablets, administered to healthy male andfemale subjects under fasting and fed conditions. Subjects were randomlyassigned to one of the three dosing sequences ABC, BCA, and CAB.Concentrations of total (racemic) methylphenidate were measured fromsamples collected over a 24-hour interval after dosing in each period.Thirty-three (33) subjects were dosed in Period 1. All 33 subjects areincluded in the safety dataset. Thirty-two (32) subjects were dosed inPeriod 2. Thirty (30) subjects were dosed in Period 3. Thirty-one (31)subjects are included in the pharmacokinetic analysis and thestatistical analyses. Subjects 10 (ABC) and 18 (CAB) completed onlyPeriod 1 of the study. These subjects were not included in thepharmacokinetic dataset. Subjects 29 (ABC) and 33 (ABC) completedPeriods 1 and 2, receiving Treatments A and B. Both subjects areincluded in the pharmacokinetic dataset.

Pharmacokinetics

The following pharmacokinetic parameters were estimated using anon-compartmental approach: C_(max), AUC_(t), AUC_(inf), AUC0-0.5,AUC0-2, AUC0-3, AUC0-4, T_(max), Kel, and T_(half).

Safety

An assessment of safety was based primarily on the frequency andseverity of AEs. There was no formal evaluation of safety ortolerability.

Statistical Methods

Descriptive statistics are estimated for the pharmacokinetic parametersin each treatment.

Analysis of variance (ANOVA) was performed on log-transformed C_(max),AUC_(t), AUC_(inf), AUC0-0.5, AUC0-2, AUC0-3, AUC0-4 and onuntransformed _(Tmax), Kel and T_(half) parameters. The significance ofthe sequence, period, treatment and subject-within-sequence effects wastested.

Using the same statistical model, the least-squares-means, thedifferences between the treatments least-squares-means and thecorresponding standard errors of these differences were estimated forlog-transformed C_(max), AUC_(t), AUC_(inf), AUC0-0.5, AUC0-2, AUC0-3,AUC0-4 parameters. Based on these statistics, the ratios of thegeometric means for treatments and the corresponding 90% confidenceintervals were calculated for the following contrasts:

-   Treatment A versus Treatment C (relative bioavailability under    fasting conditions)-   Treatment B versus Treatment A (food effect for the test    formulation)

Summary-Conclusions

Pharmacokinetic and Statistical results of MPH ER Chewable Tablets 40 mgversus Methylin® 10 mg Chewable Tablets.

MPH Geometric Mean Ratio (%) 90% Confidence Limits Intra-Sub CV (%) TestReference Lower Upper C_(max) (ng/mL) 12.1 15.1 80.0 76.3 83.9 11AUC_((0-t)) (ng.h/mL) 107.4 122.7 87.6 84.9 90.4 7 AUC_((0-inf))(ng.h/mL) 113.6 127.5 89.1 86.6 91.7 7

These statistics were used to evaluate the performance of the testformulation in relation to the reference product and the test product asfed versus fasting.

Pharmacokinetic and Statistical results of MPH ER Chewable Tablets 40mg, Fed versus Fasting study.

MPH Geometric Mean Ratio (%) 90% Confidence Limits Intra-Sub CV (%) FedFasting Lower Upper C_(max) (ng/mL) 12.6 12.1 104.1 99.4 108.9 11AUC_((0-t)) (ng.h/mL) 129.6 107.5 120.6 117.0 124.3 7 AUC_((0-inf))(ng.h/mL) 137.9 113.6 121.4 118.0 124.9 7

-   Treatment A: Methylphenidate HCl Extended Release 40 mg chewable    tablets -Fasting-   Treatment B: Methylphenidate HCl Extended Release 40 mg chewable    tablets - Fed-   Treatment C: Methylin® 10 mg chewable tablets - Fasting

Safety Results

There were no deaths, Serious Adverse Events (SAEs), or othersignificant adverse events during the conduct of this study. None of theAEs had a significant impact on the safety of the subjects or on theintegrity of the study results.

Conclusions

All treatments under either fasted or fed conditions were well toleratedby all subjects in the study. Based on the results of the study, thetest product has similar maximum and peak absorption characteristicswhen administered under fasting and fed conditions. There is nosignificant food effect on the test product.

Methylphenidate HCl 40 mg ER chewable tablets produce a mean peakconcentration 20% lower than b.i.d. administration of 20 mg of theMethylin® 10 mg product. The total exposure is similar starting atapproximately 4 hours.

All patents, patent publications, and other publications listed in thisspecification, as well as prior U.S. Pat. Application No 17/070,824,filed Oct. 14, 2020, which is a continuation of U.S. Pat. ApplicationNo. 16/700,517, filed Dec. 2, 2019, which is a continuation of U.S. Pat.Application No. 16/033,352, filed Jul. 12, 2018, now U.S. Pat.10,507,203, U.S. Pat. Application No. 15/660,046, filed Jul. 26, 2017,now abandoned, which is a continuation of U.S. Pat. Application No.15/491,547, filed Apr. 19, 2017, now US 9,844,545, U.S. Pat. ApplicationNo. 15/200,625, filed Jul. 1, 2016, which is a continuation of U.S. Pat.Application No. 15/009,468, filed Jan. 28, 2016 and U.S. Pat.Application No. 15/009,480, filed Jan. 28, 2016, both of which arecontinuations of U.S. Pat. Application No. 14/872,226, filed Oct. 1,2015, now US 9,295,642, which is a continuation of U.S. Pat. ApplicationNo. 14/624,998, filed Feb. 18, 2015, now US 9,180,100, which is acontinuation of U.S. Pat. Application No. 14/300,580, filed Jun. 10,2014, now US 8,999,386, prior International Patent Application No.PCT/US2013/054930, filed Aug. 14, 2013 and U.S. Provisional Pat.Application Nos. 61/774,783, filed Mar. 8, 2013 and 61/683,513, filedAug. 15, 2012, are incorporated herein by reference. While the inventionhas been described with reference to a particularly preferredembodiment, it will be appreciated that modifications can be madewithout departing from the spirit of the invention. Such modificationsare intended to fall within the scope of the appended claims.

1. A methylphenidate extended release chewable tablet having atherapeutically effective immediate release and a 12-hour extendedrelease profile, wherein said chewable tablet is a uniform soliddispersion comprising: (a) a sustained release methylphenidate componentcomprising a water-insoluble, water-permeable, pH-independent barriercoated, methylphenidate - ion exchange resin complex in a polymericmatrix, wherein said barrier coating is over the methylphenidate - ionexchange resin complex - matrix; (b) a first immediate release componentwhich comprises an immediate release uncoated methylphenidate - ionexchange resin complex; (c) a second immediate release methylphenidatecomponent which comprises an uncomplexed methylphenidate; wherein saidfirst immediate release component (b) has a slower onset of release than(c); wherein about 50% w/w to about 90% w/w of the methylphenidateactive component is provided by the sustained release component based onthe total amount of methylphenidate in the tablet, and wherein saidchewable tablet is capable of being divided and providing tabletportions which retain a therapeutically effective immediate release and12 hour extended release profile.